Discovery of Novel Small-Molecule Inhibitors Disrupting the MTDH-SND1 Protein–Protein Interaction

MTDH-SND1 protein-protein interaction (PPI) plays an important role in the initiation and development of tumors, and it is a target for the treatment of breast cancer. In this study, we identified and synthesized a series of novel small-molecule inhibitors of MTDH-SND1 PPI. The representative compound <b>C19</b> showed potent activity against MTDH-SND1 PPI with an IC₅₀ of 487 ± 99 nM and tight binding to the SND1-purified protein with a <i>K</i>_d value of 279 ± 17 nM. Compound <b>C19</b> significantly degraded SND1 and downregulated downstream at the protein level. Further biological evaluations suggested that compound <b>C19</b> exhibited potent activity against the proliferation of breast cancer MCF-7 cells with an IC₅₀ value of 626 ± 27 nM, significantly inhibited invasion and migration, and induced cell apoptosis. In addition, compound <b>C19</b> exhibited promising tumor growth inhibition in the xenograft model. Our study provides a potential candidate targeting MTDH-SND1 PPI for the treatment of breast cancer.